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We previously demonstrated that AngII activates MR-mediated gene transcription in human vascular smooth muscle cells (SMCs), yet the mechanism and the impact on SMC function are unknown. Using an MR-responsive element-driven transcriptional reporter assay, we confirm that AngII induces MR transcriptional activity in vascular SMCs and endothelial cells, but not in Cos1 or human embryonic kidney-293 cells. AngII activation of MR was blocked by the MR antagonist spironolactone or eplerenone and the protein kinase C-\u03b4 (PKC\u03b4) inhibitor rottlerin, implicating both in the mechanism. Similarly, small interfering RNA knockdown of PKC\u03b4 in SMCs prevented AngII-mediated MR activation, whereas knocking down of MR blocked both aldosterone- and AngII-induced MR function. Coimmunoprecipitation studies reveal that endogenous MR and PKC\u03b4 form a complex in SMCs that is enhanced by AngII treatment in association with increased serine phosphorylation of the MR N terminus. AngII increased mRNA expression of the SMC-MR target gene, FKBP51, via an MR-responsive element in intron 5 of the FKBP51 gene. The impact of AngII on FKBP51 reporter activity and gene expression in SMCs was inhibited by spironolactone and rottlerin. Finally, the AngII-induced increase in SMC number was also blocked by the MR antagonist spironolactone and the PKC\u03b4 inhibitor rottlerin. These data demonstrate that AngII activates MR transcriptional regulatory activity, target gene regulation, and SMC proliferation in a PKC\u03b4-dependent manner. This new mechanism may contribute to synergy between MR and AngII in driving SMC dysfunction and to the cardiovascular benefits of MR and AngII receptor blockade in humans.<\/jats:p>","DOI":"10.1210\/en.2019-00258","type":"journal-article","created":{"date-parts":[[2019,8,7]],"date-time":"2019-08-07T18:49:02Z","timestamp":1565203742000},"page":"2101-2114","source":"Crossref","is-referenced-by-count":16,"title":["PKC\u03b4 Mediates Mineralocorticoid Receptor Activation by Angiotensin II to Modulate Smooth Muscle Cell Function"],"prefix":"10.1210","volume":"160","author":[{"given":"Qing","family":"Lu","sequence":"first","affiliation":[{"name":"Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana P","family":"Davel","sequence":"additional","affiliation":[{"name":"Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Campinas, S\u00e3o Paulo, 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